The present invention relates to an improved plant for rapid pick and place operations, enabling automated systems that return to at least one approximately fixed position to run faster than the rate of conventional systems. The invention utilises a novel combination of robotic design, linear motor technology, and control software. The present invention further relates to a system and method for the rapid production of high-density arrays of biologically active substances.
Efficient automated systems are essential in many production processes, particularly where rapid yet accurate positioning is required for pick and place applications. For example the creation of high-density arrays of biologically active substances.
The generation of high-density arrays of biologically active substances has become an important process to assist many fields of biological research including molecular genetics and biology. Typically, a small amount of a biologically, biochemically, and/or chemically active substance, for example, nucleic acids, proteins, chemical compounds, viruses, or prokaryotic/eukaryotic cells, is transferred to a defined region on a solid carrier using an automated system. The use of an automated system allows very small regions (or spots) to be defined and generated. In this way, arrays of a multiplicity of biologically active substances can be generated at densities far greater than in the format in which the biologically active substances were stored. The substances can then be more efficiently investigated in this high density array format by a variety of physical, chemical or biological means. Such means include for example, fluorescent scanning, calorimetric reaction, ligand/anti-ligand reaction, nucleic acid hybridisation or cellular phenotype.
This approach has rapidly grown in importance and has generated a significant need for the production of many such arrays. Indeed, many research groups, academic institutions and commercial companies generate such arrays including for example, the RZPD (Germany), Clontech (USA), Research Genetics (USA), Genome Systems (USA) and Eurogentech (France).
These arrays are typically produced using a gantry robotic system carrying a transfer unit that samples (picks) one or more substances from a container and then deposits (places) the one or more substances at pre-defined positions on an appropriate carrier placed on the work surface of the robot. It is advantageous to produce many replicas of the arrays during this process, and hence the substance stored in the container may be sampled many times during the production run.
Workers skilled in the art have developed automated systems that have progressively increased the speed of these pick and place systems for the production of biological arrays. For example, Ross and co-workers (1992; In Techniques for the Analysis of Complex Genomes; Academic Press pp 137-153) described a high-density arraying robot that transferred 96 biological samples in parallel from a microtitre-plate container to a nylon filter substrate using 96 transfer pins.
An important development was the use of quadruple density microtitre plates (384 wells) and a corresponding set of 384 pins to transfer substances held in the microtitre plates (Meier-Ewert et al, 1993; Nature 254, 221-225). Recently, microtitre plates comprising 1536 wells have been produced (Greiner, Germany). However, certain biological systems (for example mammalian cell cultures) cannot be satisfactorily stored, processed or analysed at such densities, and for some applications it is necessary to use greater volumes that can be held within 1536-well (xcx9c10 xcexcl volume per well) or even 384-well (xcx9c60 xcexcl per well) microtitre plates.
As well known in the art, additional robotic developments have been made to further increase the speed of producing arrays of biologically, biochemically, and/or chemically active objects or substances. These include systems that can array over 860,000 spots in around three hours (Maier et al, 1996; In Automation Technologies for Genome Characterisation; Ed. Beugelsdijk; John Wiley and Sons pp 65-88), and the commercially available xe2x80x9cQbotxe2x80x9d (Genetix, UK). The increase in speed has been achieved in these systems simply by increasing the average velocity of robotic motion while utilising a simple pin-transfer techniques that requires the work-tool carrying the transfer-pins to return to and resample from the microtitre plate before each deposition.
Simply increasing the average velocity of robotic motion generates further problems that must be overcome. For example, a typical simple-pin transfer unit (xe2x80x9cspotting headxe2x80x9d) of a commercially available xe2x80x9cQbotxe2x80x9d comprising 384 spotting pins has a mass of approximately 2 Kg, plus the approximately 40 Kg mass of the supporting drives which generate the motion of the transfer unit. Therefore, when travelling at a speed of 2 msxe2x88x921, the inertial force (momentum) of the moving axis is approximately 90 Kgmsxe2x88x92l and has a kinetic energy of about 180 J. On acceleration and deceleration, this momentum and energy must be generated and dissipated by the drives acting on the robot frame. If insufficient dissipation is provided within the robotic frame, the whole system will shake as the transfer unit is accelerated to and decelerated from high velocity, and may even move across the floor if not securely fixed. Such shaking prevents accurate positioning of the transfer unit until the whole machine has settled, which can take over half a second per movement, losing valuable machine-time when several tens of thousand movements must be made during a single run.
It is usual in the art to minimise this problem by designing the moving mass to be substantially less than the mass of the stationary frame. Indeed, this approach is conventional automation and engineering practice. However, in order to maintain sufficient system rigidity to ensure accurate and repeatable positional accuracy, the moving axes of most high-precision positioning robots have masses exceeding several tens of Kg. This requires that the mass of the corresponding stationary frame must be substantial if the moving mass is to be accelerated to velocities greater than 1 ms xe2x88x921. For example, the overall mass of the commercial Qbot (Genetix, UK) is close to 900 kg.
Although minimising the problem of momentum and energy dissipation, such a xe2x80x9clight moving on heavyxe2x80x9d strategy soon becomes impractical. For example, a hypothetical high-precision pick and place robot designed to reach velocities of over 4 msxe2x88x921 will require a stationary mass approaching 3.5 to 5 tonnes in order to minimise positional instability due to inefficient momentum and energy dissipation. Such velocities are easily achievable using modem drive technologies. For example, Linear Drives Ltd (Essex, UK) provides a high-power small linear magnetic motor capable of providing over 400 N of peak force. Such a force is capable of accelerating a 50 kg mass from rest to 4 msxe2x88x921 within 0.5 s over a distance of 1 m.
Transfer systems other than simple pin-transfer have been developed for array production, including those described by Schober and co-workers (1993; Biotechniques 15 324-329), Shalon and co-workers (1996; Genome Res. 6 639-645 and U.S. Pat. No. 5,807,522), Cartesian (USA) Genelogic (U.S. Pat. No. 5,843,767) and Genetic MicroSystems (Rose, 1998; JALA 3 No. 3. However, these systems typically have complicated and expensive control, cleaning, engineering or fluidic systems, reducing their applicability for high-throughput array production.
Despite the development of these novel transfer techniques, the vast majority of biological arrays are still produced using simple-pin transfer. The reliability, cost and reproducibility of simple-pin transfer to produce large numbers of arrays of biologically active substances have far outweighed the disadvantage of resampling from the sampling position before each transfer. However, the speed of transfer is limited by the overall mass of the arraying systems if they are to be used at the full speed provided by contemporary robotic drive technology.
The present invention provides a system for rapid pick and place applications, that may significantly increase the speed of such procedures, particularly the production of high-density arrays of biologically active substances.